Elinzanetant, a new combined neurokinin-1/-3 receptor antagonist for the treatment of postmenopausal vasomotor symptoms

ABSTRACT

Introduction

In many postmenopausal women, quality of life is decreased due to vasomotor symptoms. Efficient and well-tolerated non-hormonal treatment options are needed.

Areas covered

The present review summarizes what is known about the etiology of postmenopausal vasomotor symptoms as a rationale for the mechanism of action of Elinzanetant, a new neurokinin (NK)-1/-3 receptor antagonist, as well as its efficacy and side effect profile.

Expert opinion

Elinzanetant likely exerts an antagonistic effect on the NK-3 receptor in the preoptic thermoregulatory zone, but also an additional antagonistic effect on the NK-1 receptor possibly leading to a reduction in vasodilatation and heat-sensing neuro-activity. Elinzanetant’s reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours. Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses. There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity. Overall, Elinzanetant seems to be well-tolerated. In the SWITCH-1 study, the 120 mg/day and 160 mg/day regimen showed good efficacy for the treatment of vasomotor symptoms and led to significant improvements in quality of life. Thus, 120 mg oral Elinzanetant/day was used in phase III trials, whose results have not yet been published.

KEYWORDS:

• Menopause
• neurokinin
• NT-814
• sleep
• vasomotor symptoms

1. Introduction

The loss of estrogen production, which occurs during menopause due to the depletion of ovarian follicles, results in vasomotor symptoms. Notably, up to three-fourth of women above the age of 50 experience from menopause-associated symptoms, which is also associated with a decrease in the quality of life [1–3]. Hot flashes are not only the most common symptom of the climacteric syndrome but are also the number one cause for seeking medical attention in this context [4,5]. Hot flashes are defined as transient sensations of heat, sweating, flushing, anxiety, and chills, lasting for one to five minutes. On average, women are affected for up to 10 years [6–8]. Notably, there is an association with night-time awakenings, which then lead to insomnia and fatigue [9–11].

The therapy in moderate to severe cases is menopausal hormone treatment (MHT), previously called hormonal replacement therapy (HRT), with estrogen or a combination of estrogen and a progestin. However, these hormonal treatments may increase the risk of conditions including venous thromboembolism (VTE), major coronary heart disease, stroke, breast cancer, endometrial cancer, and ovarian cancer [12]. Although the risk constellations are only moderate and depend on patient-specific factors, type of treatment used, treatment duration, and others [13–15], many women refrain from using MHT due to concern about side effects [16]. Moreover, there are several situations, where MHT is contraindicated, which include but are not restricted to high-risk constellations for breast cancer/heart disease/VTE and history of stroke/myocardial infarction/or pulmonary embolism [12]. Notably, it was shown recently that quite a few women who experienced moderate to severe vasomotor symptoms did not seek healthcare advice. The main reasons for not having taken MHT so far were the belief that menopause would pass by itself, worries about side effects and long-term risks, lack of information about MHT, and risk factors in the family [16]. Another recent study provided similar results and also showed that physicians often were worried about risks and side-effects of MHT [17].

Given the above-mentioned decrease in quality of life and the negative impact on daily activities associated with postmenopausal hot flashes and sleep disturbances [1–3], non-hormonal treatment options are needed. One of the most promising new substances is Elinzanetant, also called ‘NT-814,’ which is a novel, selective antagonist of both neurokinin-1 and −3 (NK-1, NK-3) receptors [18]. The development of this substance was based on findings, which suggested a functional role for NK receptor systems in the etiology of hot flashes through hypothalamic mechanisms [19–21].

The focus of this narrative review will be on etiologic considerations, which are relevant for the mechanism of action of Elinzanetant, and the first clinical studies about the substance and its efficacy.

2. Pathophysiologic considerations of vasomotor symptoms

One important precondition for the non-hormonal treatment of vasomotor symptoms is a good understanding of the underlying phenomena. There have been many hypotheses about the etiology, which included a narrowed thermoneutral zone [22], altered central concentrations of neurotransmitters including serotonin and noradrenaline [23], and modulation of the thermoregulatory pathway [24,25].

However, in 1979, the observation was made that the menopausal flashes would synchronize with the onset of the luteinizing hormone (LH) pulses [26,27]. Although this observation has been challenged recently [28], these findings have been hinting at neuroendocrine involvement for a long time. NK receptors are rhodopsin-like 7 transmembrane Gq-coupled receptors and are activated by NK A, NK B, and Substance P (the endogenous ligand for the NK-1 receptor), which belong to the NK/tachykinin family of neurotransmitter peptides [29]. Based on the co-localization of kisspeptin, NK-B with its NK-3 receptor, and the opioid neuropeptide dynorphin (Dy), the affected group of hypothalamic neurons was named ‘KNDy’ neurons. The role of KNDy neurons as main regulators of reproductive processes in mammals via control of Gonadotropin Releasing hormone (GnRH) has been well described [30,31].

Notably, neuronal hypertrophy has been shown in the hypothalamus of postmenopausal monkeys in 1966 [32] and was also observed in postmenopausal women [33,34]. This is also accompanied by a hypothalamic overexpression of NK-B, substance P, and kisspeptin [33,34]. It is believed that these alterations are secondary to the loss of estrogen since the same changes have been shown in young cynomolgus monkeys after ovariectomy, whereas this phenomenon could not be found in women who received estrogen replacement therapy [34]. Of relevance, the KNDy neurons project to the preoptic thermoregulatory zone, which expresses the NK-3 receptor, as reviewed by Rance et al. [35]. These findings were supported by the reports that intravenous NK-B administration caused hot flashes in women [36] and that infusion of substance P led to face and neck flashing in men [37].

3. NK-3 receptor antagonists other than Elinzanetant

The efficacy of NK-3 receptor antagonists has also been demonstrated for substances other than Elinzanetant. In short, a phase 2, randomized, double-blind, placebo-controlled, single-center, crossover trial on Palvinetant showed that the substance significantly reduced the total weekly number of hot flashes by 45% points (95% CI 22–67) with an adjusted estimate of difference between Palvinetant and placebo of 29.66 (p < 0.0001) [38]. Similar results were found for Fezolinetant. After the first phase 2 clinical trials, which already demonstrated the substance’s efficacy [39,40], two phase III randomized controlled studies (SKYLIGHT 1 and SKYLIGHT 2) showed that both finally evaluated doses (30 mg and 45 mg) significantly reduced the frequency and the severity of vasomotor symptoms at weeks 4 and 12 [41,42].

4. General and pharmacological details about Elinzanetant

Elinzanetant, initially developed as GSK1144814 (Box 1), was acquired by Bayer ® as ‘NT-814’ [43]. Its chemical structure is shown in Figure 1 One main relevant characteristic is its antagonistic activity of both the NK-1 and NK-3 receptors. Antagonism at both the NK-3 and NK-1 receptors is relevant to the efficacy of Elinzanetant. The NK-3 receptor with its main ligand NK-B is well described in the etiology of hot flashes. The primary ligand of the NK-1 receptor is substance P, which, as mentioned above, is overexpressed in the hypothalamic neurons of postmenopausal women. One could hypothesize that the additional NK-1 receptor antagonism may increase the efficacy of Elinzanetant by a reduction in vasodilatation and in heat-sensing neuro-activity, when compared to NK-3 antagonism only. However, this has not been proven to date [43]. In addition, phase II trials suggested that specific NK-1 receptor antagonists would be effective in reducing depressive symptoms, at least in patients with major depressive disorder [44], and in improving sleep maintenance, which was shown in primary insomnia patients [45]. Thus, Elinzanetant may offer additional benefit to postmenopausal women with climacteric syndrome.

Figure 1. Chemical structure of Elinzanetant (NT-814) [44].

Concerning pharmacologic aspects, it has been shown that GSK1144814 would occupy the NK-1 receptor in a dose-dependent manner with a median effective concentration (EC₅₀) estimated in vivo of about 0.9 ng/mL in the human brain. Notably, a direct relationship was observed between the plasma concentration and NK-1 receptor occupancy in the brain, which suggested that the occupancy of brain receptors should be accurately assessed by measured plasma concentrations [46]. In alcohol-intoxicated volunteers, it has been shown that GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of the substance with alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, and other parameters to a small amount, compared to alcohol alone. Thus, one can assume that the effect of Elinzanetant is selective for NK-1 and NK-3 receptors [47]. Moreover, previous studies had shown peak drug concentrations within one hour of administration and a terminal elimination half-life of approximately 15 hours [48].

As already reported, there is no easily applicable and reliable biomarker for (post-)menopausal vasomotor symptoms [43]. Due to the previously mentioned synchrony between LH pulses and hot flashes [26,27], one could use LH levels as a surrogate parameter for pharmacodynamics of NK receptor antagonists. In a randomized, placebo-controlled study of 33 premenopausal women who received the substance for one menstrual cycle, Elinzanetant was shown to lower serum LH, estradiol, and luteal-phase progesterone in a dose-dependent manner [48]. Details about the study design are provided in Table 1.

Table 1. Overview about clinical studies on Elinzanetant.

Author, year	Pawsey et al., 2021	Trower et al., 2020	Simon et al., 2023
Reference	[44]	[45]	[46]
Study name	–	RELENT-1	SWITCH-1
Clinical trial registry number	ISRCTN11913515	NCT02865538	NCT03596762
Clinical trial phase	I	IIb	IIb
Inclusion criteria	Premenopausal women	Postmenopausal women
	18–45 years	40–65 years
	Healthy, ovulatory women	7–20 moderate to severe hot flashes/day	≥7 moderate hot flashes/day
Number of randomized subjects	33	76	199
Route of administration	Oral	Oral	Oral
Elinzanetant doses	Placebo	Placebo	Placebo
	40 mg/80 mg/ 120 mg per day	50 mg/100 mg/ 150 mg/300 mG per day	40 mg/80 mg/ 120 mg/160 mg per day
Treatment duration	1 menstrual cycle	14 days	12 weeks
Primary endpoint	FSH, LH, estradiol serum levels	Safety	Frequency and severity of hot flashes
Secondary endpoint	–	Number and severity of hot flashes	Frequency and severity of hot flashes, sleep quality, ISI, PSQI, and MenQoL-I scores

Abbreviations used: ISI, Insomnia Severity Index questionnaire; PSQI, Pittsburgh Sleep Quality Index, MenQol-I, Menopause-specific Quality-of-Life questionnaire intervention.

5. Clinical data about Elinzanetant

To date, two phase II clinical trials on postmenopausal women have been published, namely the RELENT-1 study [18] and the SWITCH-1 study [49]. One phase I study was performed on premenopausal women [48]. Table 1 shows an overview of these studies’ designs.

5.1. Safety profile in postmenopausal women

In the RELENT-1 study, there was a similar overall adverse event incidence in all study groups (46.7% − 73.3%) except in the 300 mg dose group (84.6%). The rate of adverse events related to the study medication was also highest in this group. The most common adverse events were mild somnolence and headaches, followed by diarrhea and pelvic pain. The majority of women who reported somnolence, which was always mild and commonly intermittent, experienced this symptom only during the inpatient phase of the study. Contact dermatitis was also common but derived from ECG electrode attachment and, thus, was not specific for Elinzanetant [18].

In the larger SWITCH-1 study, 67.8% of participants in the Elinzanetant groups reported treatment-emergent adverse events compared to 60% in the placebo group. Again, the most frequently reported adverse events were headache, somnolence, and diarrhea. Study medication-related adverse events led to discontinuation of treatment in 4.6% of Elinzanetant-treated participants (7/152). The reasons included prolonged QT and bradycardia, increased liver function test, headache, somnolence, abdominal distension, dyspepsia, fatigue, depression and anxiety, and erythema multiforme [49]. An overview of the three most common drug-related adverse events in provided in Table 2.

Table 2. Overview of the most common treatment-specific adverse events of Elinzanetant in the RELENT-1 [45] and SWITCH-1 [46] studies.

	RELENT-1 [45]				SWITCH-1 [46]
Adverse event	50 mg	100 mg	150 mg	300 mg	40 mg	80 mg	120 mg	160 mg	Pooled incidence
N	15	15	15	13	31	17	52	52	210
Somnolence	5 (33.3)	2 (13.3)	5 (33.3)	9 (69.2)	0	2 (11.8)	0	5 (9.6)	28 (13.3)
Headache	0	5 (33.3)	1 (6.7)	6 (46.2)	3 (9.7)	2 (11.8)	6 (11.5)	4 (7.7)	27 (12.9)
Diarrhea	1 (6.7)	0	1 (6.7)	3 (23.1)	2 (6.5)	2 (11.8)	3 (5.8)	3 (5.8)	15 (7.1)

Data are provided as n (%).

A particular concern might be the elevation of liver enzymes. Notably, the U.S. Food & Drug Administration (FDA) already approved the use of the NK-3 receptor antagonist Fezolinetant (trade name: Veozah ®) for the treatment of moderate to severe vasomotor symptoms caused by menopause. However, the FDA warrants that the prescribing information must include ‘a warning for elevated hepatic transaminase, or liver injury. Before using Veozah®, patients should have blood work done to test for liver damage. While on Veozah®, routine bloodwork should be performed every three months for the first nine months of using the medication [50]. A recent meta-analysis on Fezolinetant showed a statistically insignificant, increasing trend for hepatotoxicity in the treatment group [51]. It seems reasonable that a combined NK-1 receptor and NK-3 receptor antagonist could reveal a similar risk profile. In the RELENT-1 study, the following details about increases in the alanine aminotransferase were reported: in one participant, it increased to 1.3 × upper limit of normal (ULN) on day 8 and decreased to 1.1 × ULN on day 14; to 2.6 × ULN on day 8 in another patient with a decrease to 1.4 × ULN on day 14. Two other participants, who received Elinzanetant, had similar changes, which were not reported as adverse events. In total, the incidence was 6.9% (4/58), compared to 11.1% (2/18) in the placebo group [45]. In the SWITCH-1 trial (n = 152), some sporadic increases in transaminases during treatment were also observed (<3 × ULN). Notably, the incidence and magnitude were equal in the placebo and Elinzanetant groups (11% and 8.8%, respectively). In addition, two participants randomized to Elinzanetant (both 80 mg) revealed increases in transaminases ≥3 × ULN but had no detectable Elinzanetant in plasma samples drawn at the same time. Thus, it was concluded that there was no evidence of drug-related hepatotoxicity [49].

5.2. Clinical efficacy

In the RELENT-1 trial, where Elinzanetant/placebo was given for only 14 days, improvements in hot flash frequency, severity, and severity score, as well as in the frequency of waking due to night sweats were seen in all groups, which also included the placebo group. Notably, participants had to recall the number and severity (mild, moderate, or severe) of all hot flashes experienced and recorded these twice daily in paper diaries for 14 days before treatment start, for the two weeks of treatment and on the morning of day 15. Notably, there were greater reductions in the second treatment week than in the first. Concerning the frequency of moderate/severe hot flashes, the mean reduction at week 2 was 37% in the placebo group compared to 24% in the 50 mg group (p = 0.024 versus placebo), 59% in the 100 mg group (p = 0.155), 84% in the 150 mg group (p < 0.001), and 66% in the 300 mg group (p = 0.022). A similar pattern was observed for the frequency of waking due to night sweats. For all outcome parameters concerning efficacy, mean improvements were greatest in the 150 mg and 300 mg groups and smallest in the placebo and 50 mg groups [18].

In the SWITCH-1 study, Elinzanetant/placebo was given for 12 weeks. E-diaries were used to record the frequency and severity of vasomotor symptoms and the number of secondary nighttime awakenings twice daily. Severity was scored as none, mild (sensation of heat without sweating), moderate (sensation of heat with sweating but able to continue activity), and severe (sensation of heat with sweating, causing cessation of activity, with any vasomotor symptoms causing nighttime awakening being considered as severe. Significant reductions in the mean daily frequency of moderate-to-severe vasomotor symptoms were found for Elinzanetant over placebo at doses of 120 mg (weeks 1, 4 and 12; p-values ranging from 0.006 to 0.049) and 160 mg (weeks 1 and 4; p = 0.001). Notably, the improvements tended to increase throughout treatment and showed a return toward baseline 4 weeks after treatment discontinuation. Comparable results were found for the secondary outcome measures, the Insomnia Severity Index questionnaire (ISI), the Pittsburgh Sleep Quality Index (PSQI) total score, and the Menopause-specific Quality-of-Life questionnaire intervention (MenQol-I). Significant improvements in the ISI were found at weeks 4 and 12 with both 120 mg and 160 mg (p < 0.001). Clinically meaningful improvements (a minimum reduction of at least 6 points) were achieved at weeks 8 and 12 for 120 mg and at week 12 for 160 mg. Significant improvements in the PSQI total score were observed at weeks 4 and 12 in the 120 mg and 160 mg groups, compared to placebo. A statistically significant improvement in MenQol-I was found for Elinzanetant 120 mg compared to placebo at weeks 4 and 12. However, clinically meaningful improvements (at least a deduction of 1 point) were observed in the 120 mg and 160 mg groups at weeks 4, 8, 12, and 16 [49]. Given these data, it seems reasonable that the dose of 120 mg was chosen for phase III studies (see below).

6. Future prospects

At present (NaN Invalid Date NaN), 19 trials on Elinzanetant are registered in the Clinical Trials registry (ClinicalTrials.gov). The majority of them completed (n = 16), two of them active, and one recruiting. Notably, several phase III studies are underway or have already been completed, which evaluated 120 mg Elinzanetant versus placebo in a double-blinded randomized manner (OASIS-1, NCTOS042362, 26 weeks; OASIS-2, NCT05099159, 26 weeks; OASIS-3, NCT05030584, 52 weeks; and OASIS-4, NCT05587296, 52 weeks). Whereas the OASIS 1–3 studies were conducted in general postmenopausal women, the OASIS-4 trial includes women vasomotor symptoms caused by adjuvant endocrine therapy for the treatment of hormone receptor-positive breast cancer. In the NIRVANA trial (NCT06112756) the focus is on Elinzanetant’s efficacy on menopausal sleep disturbances.

Notably, Bayer ® already announced ‘positive top line results’ about the OASIS 1–3 studies on their web-page and submission of these results to health authorities for approval of marketing authorizations [52].

7. Conclusion

It already seems likely that, in addition to all available treatment options, which include but are not limited to MHT, phytoestrogens and Fezolinetant, Elinzantenat will be an effective treatment option for (post-)menopausal vasomotor symptoms and sleep disturbances.

8. Expert opinion

In our humble opinion, the new substance Elinzanetant could have a relevant impact on the treatment of menopausal vasomotor symptoms as well as sleep disturbances, since a new non-hormonal option can be offered to affected patients. This will be a substantial improvement, since many women do not want to use hormones. In addition, there are many patients, who are not allowed to use menopausal hormone treatment for contraindications. First and foremost, this includes women at risk for breast cancer or after breast cancer. The fact that a large study of this special population is planned, is of utmost relevance. Data about the safety of new non-hormonal treatment options for vasomotor symptoms are necessary. In other words, it needs to be demonstrated that the drug is safe regarding the risk of recurrence of breast cancer. Vasomotor symptoms are of high clinical relevance for the affected women and lower their quality of life to a substantial amount. The availability of efficient and well-tolerated non-hormonal treatment options will have quite an impact presumably. First, more women who are afraid of the long-term effects of MHT might seek medical help for vasomotor symptoms. Second, it can be assumed that these treatment options will also be included in treatment guidelines, given that several phase 3 clinical trials will be available about the efficacy and safety of Elinzanetant in the future. If the previous results of the phase 2 studies will be confirmed, the substance could be ranked as ‘efficiant for vasomotor symptoms’ with a ‘low risk for treatment discontinuation and adverse events.’ However, one should also be aware of the fact that Elinzanetant does not affect other symptoms and consequences of postmenopausal estrogen and androgen deficiency, which include prevention of loss of bone mass, vaginal dryness, and hypoactive sexual desire disorder. Thus, it must be stated clearly that it is unlikely that MHT will be replaced by the new neurokinin receptor antagonists. This circumstance is probably the most relevant weakness of this group of substances. In other words, Elinzanetant is another treatment option, but surely not the solution for all problems that burden women in their postmenopausal years.

One might suggest that one goal of future research could be to focus on individual treatment options depending on an individual’s specific needs. Moreover, one could also aim to find evidence for combinations of neurokinin receptor antagonists with low-dose MHT and/or local estrogen/androgen therapy in order to maximize treatment effect and minimize the potential for side effects and negative long-term health consequences.

In our opinion, data about the use of Elinzanetant for sleep disorders and its safety concerning breast cancer will revolutionize this medical field. Women who are at risk for breast cancer or have suffered from it are a group of patients who have not received adequate treatment for vasomotor symptoms despite the availability of other non-hormonal treatment options. Moreover, especially patients after breast cancer on anti-hormonal treatment often suffer from severe hot flashes, sleep disturbances, and, thus, decreased quality of life. These are among those women who might benefit the most from the new neurokinin receptor antagonists.

All in all, although Elinzanetant might only be one more treatment option for vasomotor symptoms, it enriches the whole field tremendously and all physicians who carer for women burdened by postmenopausal vasomotor symptoms should look forward to the upcoming results of the long awaited phase 3 trials.

Drug Summary Box.

Drug name (generic): Elinzanetant

Phase (for indication under discussion): 2

Indication (specific to discussion): (post-) menopausal vasomotor symptoms

Pharmacology description/mechanism of action: combined neurokinin-1/-3 receptor antagonist

Chemical structure: 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1c] [1,4]oxazin-8(1 H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide

Pivotal trials: RELENT-1 (2 weeks treatment duration)

[18] Trower M, Anderson RA, Ballantyne E, Joffe H, Kerr M, Pawsey S. Effects of NT-814, a dual neurokinin 1 and 3 receptor antagonist, on vasomotor symptoms in postmenopausal women: a placebo-controlled, randomized trial. Menopause. 2020 May;27(5):498-505. doi: https://doi.org/10.1097/GME.0000000000001500.

SWITCH-1 (12 weeks treatment duration).

[49] Simon JA, Anderson RA, Ballantyne E, et al. Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1). Menopause. 2023;30(3):239-246. doi: https://doi.org/10.1097/GME.0000000000002138.

Article highlights

• Elinzanetant is a new neurokinin (NK)-1/-3 receptor antagonist for the treatment of menopausal vasomotor symptoms.

• Elinzanetant’s reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours.

• Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses.

• There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity.

• Elinzanetant seems to be well-tolerated and efficient in reducing the severity and frequency of hot flashes.

Declaration of Interest

J Ott declares receiving fees for lecturing from Bayer, Lenus Pharma, Exeltis, and Gedeon Richter. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer of this manuscript has disclosed being on the Advisory boards for Bayer and Astellas. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.